title: CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation.
abstract: Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1β (IL-1β) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-β and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1β production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1β and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Sheedy
authors.forename: Alena
authors.initials: A
authors.lastname: Grebe
authors.forename: Katey J
authors.initials: KJ
authors.lastname: Rayner
authors.forename: Parisa
authors.initials: P
authors.lastname: Kalantari
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.forename: Susan B
authors.initials: SB
authors.lastname: Carpenter
authors.forename: Christine E
authors.initials: CE
authors.lastname: Becker
authors.forename: Hasini N
authors.initials: HN
authors.lastname: Ediriweera
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Stuart
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology*; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology*; D018955:CD36 Antigens / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D058847:Inflammasomes / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D008077:Lipoproteins, LDL / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018955:CD36 Antigens; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008077:Lipoproteins, LDL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C099252:oxidized low density lipoprotein; D012313:RNA